A missile therapy including binding an antitumor compound such as chemotherapeutic agent, radioisotope, toxin and the like to a monoclonal antibody against an antigen specifically expressed in cancer cells, and selectively delivering same to the target has entered a practical stage. In the missile therapy, side effects of an antitumor compound are expected to be reduced, since it is possible to selectively attack cancer tissues while suppressing uptake of the antitumor compound by normal cells. As an antibody used in the missile therapy targeting cancer, KADCYLA (Trastuzumab Emtansine) and the like are known. Since there are a variety of cancer cells, it is desirable to have many variations of antibodies useful for the missile therapy to be able to deal with the antigen expression pattern of target cancer cells.
ADAM proteins (ADAMs: a disintegrin and metalloproteinases) are multifunctional proteins involved in the ectodomain shedding of transmembrane proteins, cell adhesion and infiltration (non-patent documents 1, 2). The human genome contains 25 ADAMs including four pseudogenes and 21 kinds of ADAMS are composed of 13 kinds of proteolytic ADAMs that exhibit proteolytic activity and 8 kinds of non-proteolytic ADAMs (non-patent documents 1, 3). Proteolytic ADAMs share the metalloproteinase domain of matrix metalloproteinases (MMPs), and a typical proteolytic ADAM protein comprises propeptide, metalloproteinase, disintegrin-like, cysteine-rich, epidermal growth factor-like, transmembranes and cytoplasmic domains (non-patent documents 3-9). Many proteolytic ADAMs, including ADAM8, ADAM9, ADAM12, ADAM15, ADAM17, ADAM19 and ADAM28 are overexpressed in human cancers and are associated with tumor growth and progression (non-patent documents 5, 9). The present inventors' previous studies have indicated that ADAM28 (also known as ADAM metallopeptidase domain 28), which has two alternative isoforms, including a prototype membrane-anchored form (ADAM28m) and a short secreted form (ADAM28s) (non-patent documents 5, 10, 11), is abundantly expressed in human non-small cell lung carcinoma and breast carcinoma (non-patent documents 12, 13). By in situ hybridization and immunohistochemistry, the present inventors have demonstrated that ADAM28 is expressed predominantly in carcinoma cells contained in carcinoma tissues and that ADAM28 mRNA expression levels are associated with the cellular proliferation of breast cancer (non-patent document 13) and with both proliferation and infiltration of cancer cells in non-small cell lung cancer (non-patent document 12). In a parallel study, the present inventors showed that serum ADAM28 levels in non-small cell lung cancer patients substantially increase with the progression of tumor, lymph node metastasis, and cancer recurrence (non-patent document 14). These data imply that ADAM28 is involved in cell proliferation and metastasis particularly in human cancer. The present inventors have demonstrated that ADAM28 contributes to cancer cell proliferation through increased bioavailability of insulin-like growth factor-I (IGF-I) by selective digestion of IGF-binding protein-3 (IGFBP-3) in IGF-I/IGFBP-3 complex (non-patent document 13), and to angiogenesis by digestion of connective tissue growth factor in breast cancer (non-patent document 15).
The present inventors obtained an anti-human ADAM28 antibody showing a superior proliferation suppressive effect and a cancer metastasis inhibitory effect against cancer cells (patent document 1).